Senkyunolide I suppresses hepatic stellate cell activation and liver fibrosis by reprogramming VDR-dependent fatty acid metabolism

Hepatic stellate cells (HSCs) activation represents a central pathological mechanism in liver fibrosis, with emerging evidence implicating fatty acid metabolic reprogramming as a critical regulator of this process. Our study established the vitamin D receptor (VDR) as a key transcriptional coordinator of fatty acid metabolism during HSC activation. Genetic VDR deletion in mice exacerbated liver fibrosis progression, which was associated with elevated TGF-β1 levels and increased SMAD3 phosphorylation. Mechanistically, VDR deficiency disrupted lipid homeostasis through the upregulation of lipogenic Enzymes (fatty acid synthase, Acetyl-CoA Carboxylase 1, ATP Citrate Lyase) and desaturases (stearoyl-CoA desaturase-1, fatty acid desaturases 1/2) and the suppression of the β-oxidation gatekeeper carnitine palmitoyltransferase 1A (CPT1A). Pathological VDR downregulation was observed in both TGF-β1-activated HSCs and fibrotic liver tissues, suggesting a disease-associated regulatory circuit. Calcitriol-mediated VDR activation reversed TGF-β1-induced SMAD3 phosphorylation and normalized metabolic enzyme expression, effectively reducing lipid accumulation and Collagen deposition. We further identified senkyunolide I as a novel natural VDR agonist that rebalances fatty acid metabolism by simultaneously downregulating lipogenesis/desaturation machinery and upregulating CPT1A. The complete abolition of anti-fibrotic effects of senkyunolide I following VDR knockdown confirmed its strict receptor dependency. These findings identify VDR as a master regulator of metabolic reprogramming in HSC activation and validate pharmacological VDR activation as a promising therapeutic strategy for liver fibrosis. The dual metabolic regulatory capacity of senkyunolide I through VDR signaling highlights its potential for targeted antifibrotic intervention.

Fatty acid metabolism reprogram; Hepatic stellate cells; Liver fibrosis; Senkyunolide I; Vitamin D receptor.